Project Summary Dietary Restriction (DR) is the most robust environmental method to slow aging and age-related diseases in species as diverse as yeast, worms, fruit flies and rodents. Research in invertebrates has made invaluable contributions to this field. A novel concept emerging from this proposal is the critical role of the intestine in modulating the protective effects of DR on healthspan through modulating intestinal permeability. Importantly, we identify a novel role for enterocyte cell death in mediating the effects of diet and age on intestinal homeostasis. A growing number of disorders including Inflammatory bowel disease (IBD), HIV, colorectal cancer, chronic heart failure, cancer and Parkinson?s disease have been linked to compromised intestinal integrity thus underscoring the importance of the gut epithelium in human health and disease. However, the lack of adequate animal models that mimic gut intestinal disorders hamper a better understanding and development of therapeutics in this area. The complex anatomical, physiological and behavioral characteristics, the relatively short lifespan, and powerful genetic tools that allow the rapid discovery of new genes are some of the unique strengths that make D. melanogaster an ideal model to study how the intestine influences healthspan in response to nutritional variation. We hypothesize that age and a rich diet enhances intestinal permeability and limits lifespan by increasing enterocyte damage and cell death. We observed that inhibition of dMyc, enhances, enterocyte cell death, intestinal permeability, and limits lifespan. Cell competition is an important mechanism by which neighboring cells remove unfit cells to maintain tissue homeostasis. In Aim 1 we will characterize the role of dMyc in mediating cell death by ?cell competition? to modulate intestinal homeostasis. We hypothesize that excessive cell death due to cell competition if unrepaired can cause an age-dependent increase in intestinal permeability. In Aim 2 we will characterize candidates from a genetic screen that has uncovered novel modulators of diet and age-dependent changes in enterocyte cell death. We will characterize their role in cell competition, barrier function, repair, and lifespan. In Aim 3 we will investigate potential mechanisms for age-related changes in gut barrier dysfunction and enterocyte apoptosis. In particular, we will explore alterations in mitochondrial function as a driver of age and diet-dependent changes in enterocyte cell death. As the intestinal biology and the molecular pathways explored in this proposal are well conserved from flies to humans, the insight generated will aid in our understanding of intestinal homeostasis and its impact on longevity and gut function related diseases in humans.